Kesavaperumal Gopalakrishnan

Rett syndrome (RTT) is an X-linked neurodevelopmental disorder arising predominantly from de novo loss-of-function mutations in MECP2, affecting approximately 1 in 10,000 live female births. MECP2 is a dosage-sensitive epigenetic regulator acting through its methyl-CpG-binding (MBD) and transcriptional-repression (TRD) domains; isoform-specific expression and X-chromosome-inactivation mosaicism drive the wide phenotypic variability, with mutation type broadly correlating with severity. Although historically viewed as neuron-centric, RTT is a multisystem disorder: beyond psychomotor regression, stereotypic hand movements, gait apraxia, and loss of spoken language, MECP2 deficiency contributes to brainstem-mediated breathing dysrhythmia, QTc prolongation, enteric dysmotility, low bone density, and mitochondrial/metabolic deficits, amplified by glial–neuronal crosstalk. Preclinical models, MECP2 rodents, patient iPSC-derived neurons, and cerebral organoids, reveal synaptic and dendritic deficits that improve substantially when MECP2 is reactivated in these systems, indicating that MECP2-deficient neurons remain viable rather than degenerating; whether comparable improvement can be achieved in affected individuals is not yet established. The therapeutic landscape now spans multidisciplinary supportive care, the first approved pharmacotherapy trofinetide, AAV-mediated MECP2 gene replacement (now in pivotal trials, with an important gene-therapy safety signal), antisense oligonucleotides for dosage normalisation, and emerging metabolic agents; validated biomarkers and objective outcome measures remain a major unmet need. Conclusion: RTT is a multisystem monogenic disorder whose management is shifting from symptom control toward disease modification. Phenotypic rescue after MECP2 restoration in rodent models provides the rationale for this shift but does not establish that RTT is reversible in patients; progress now depends on validated biomarkers, dose-controlled disease-modifying therapies, long-term outcome data, and equitable global access. Graphical abstract Integrated overview of Rett syndrome (RTT) from molecular cause to equitable translation. 1 MECP2 as a dosage-sensitive epigenetic reader encoded at Xq28, where a loss-of-function MECP2 variant impairs methylated-DNA binding and chromatin regulation and disrupts transcriptional, splicing, and synaptic gene networks; the MECP2-E1 (492 amino acids) and MECP2-E2 (486 amino acids) isoforms differ in distribution, and severity is modified by mutation type, residual function, and X-chromosome-inactivation mosaicism. Because too little MECP2 causes RTT while too much is also pathogenic, restoration must be dose-controlled, cell-aware, and brain-wide. 2 RTT extends well beyond the central nervous system, direct peripheral effects combining with brainstem autonomic dysfunction to involve brain and glia, breathing, cardiac, gastrointestinal, skeletal and metabolic systems, across the characteristic four-stage clinical trajectory. 3 A therapeutic landscape moving from whole-person supportive care toward controlled gene restoration, spanning trofinetide (modest symptom-level benefit), AAV gene replacement (milestone gains in uncontrolled single-arm programmes, with expression control and immune safety critical after a fatal high-dose event in 2024), and earlier-stage antisense, X-reactivation, editing, and small-molecule approaches. No approach has yet demonstrated reversal of established deficits in humans. 4 Translation, safety, and equitable access as the rate-limiting step, from earlier genetic diagnosis through registry-based natural-history data and biomarker-guided trials to equitable access What is Known: • More than 90–95% of classic Rett syndrome is caused by de novo loss-of-function mutations in MECP2, a dosage-sensitive epigenetic reader whose isoform distribution, residual function and X-chromosome-inactivation mosaicism together account for much of the phenotypic variability. • Reactivating MECP2 in symptomatic adult rodents substantially improves many disease features, establishing that MECP2-deficient neurons are functionally impaired rather than lost and providing the rationale for disease-modifying therapy. What is New: • This review integrates isoform-specific and non-neuronal (glial, respiratory, cardiac, gastrointestinal, skeletal and metabolic) mechanisms with a literature base updated to 15 August 2026, and identifies the continuing absence of any validated biomarker or surrogate endpoint, rather than target identification, as the principal obstacle to efficient trials. • It critically appraises the post-trofinetide landscape — divergent FDA and EMA assessments of the same trial data, a fatal high-dose AAV hyperinflammatory event, and single-arm registrational gene-therapy programmes reported largely outside peer review — and concludes that the demonstrated outcome to date is gain or re-acquisition of developmental milestones, not reversal of established disease.

Rett syndrome (RTT), an X-linked neurodevelopmental disorder predominantly arising from de novo MECP2 mutations, manifests with psychomotor regression, stereotypic hand movements, gait apraxia, and expressive aphasia, driven by dosage-sensitive epigenetic dysregulation via MeCP2's methyl-CpG-binding domain (MBD) and transcriptional repression domain (TRD). Isoform-specific expression (MeCP2-E1 neuronal predominance) and X-chromosome inactivation mosaicism underpin phenotypic variability, with missense (R133C, T158M) and nonsense (R168X, R255X) variants correlating to severity gradients. Multisystem pathophysiology encompasses brainstem-mediated respiratory dysrhythmias, QTc prolongation via ion channel perturbations, enteric hypomotility, osteopenic fractures, and mitochondrial bioenergetic deficits, exacerbated by glial-neuronal crosstalk and oxidative stress. Preclinical platforms, including Mecp2-null rodents, patient-derived iPSCs, and cerebral organoids, elucidate synaptic hyperexcitability, dendritic arborization deficits, and reversibility upon Mecp2 reactivation. Therapeutic modalities span supportive multidisciplinary interventions, FDA-approved trofinetide (IGF-1 analog modulating neurotrophic cascades), AAV-mediated gene replacement (NGN-401, TSHA-102 with miRARE autoregulation), ASOs for dosage normalization, and emerging PPAR-γ agonists targeting metabolic homeostasis. Prioritized research agendas emphasize validated biomarkers (BDNF/IGF-1 axes, miRNA signatures), combinatorial regimens, and equitable global access to mitigate caregiver burden and phenotypic heterogeneity.

Colorectal carcinoma (CRC) exerts a growing global disease burden, with microsatellite-stable/proficient mismatch repair (MSS/pMMR) tumors exhibiting intrinsic refractoriness to immune-checkpoint blockade (ICB) owing to low tumor mutational burden, limited neoantigenicity, and an immunosuppressive tumor microenvironment (TME) dominated by regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs). This review evaluates induced pluripotent stem cell (iPSC)–derived polyvalent vaccines as ontogenetically recapitulative immunogens capable of reinstating broad antitumor immunity. Reprogramming induces re-expression of oncofetal tumor-associated antigens, including cancer-testis antigens (NY-ESO-1, MAGE-A3), aberrant glycoforms of CEA and MUC1, and clinically actionable neoepitopes such as KRAS^G12D/V, thereby promoting epitope spreading and immunogenic cell death. Irradiated autologous or syngeneic iPSCs, delivered with Toll-like receptor 9 agonists, facilitate robust MHC I/II cross-presentation, driving CD8⁺ cytotoxic T-cell activation, Th1 polarization, perforin/granzyme-mediated cytolysis, and favorable effector-to-suppressor ratios. Preclinical models of melanoma, pancreatic ductal adenocarcinoma, and MSS CRC demonstrate prophylactic and therapeutic efficacy, with neoantigen-enhanced iPSCs synergizing with radiotherapy-induced DAMPs to achieve durable regressions and memory T-cell formation. Translational priorities include CRISPR-engineered hypoimmunogenic iPSC platforms, GMP-compatible non-integrating reprogramming, and combinatorial integration with STING agonists, ICB, CAR-NK cells, and LNP-mRNA constructs to enable biomarker-guided clinical deployment in minimal-residual-disease CRC.